The concept of preventing sexual transmission of the human immunodeficiency virus (HIV) infection via pre- exposure prophylaxis (PrEP) with antiretroviral drugs (ARV) has been clinically proven, yet its implementation remains difficult, as poor adherence has repeatedly confounded clinical progress. Individuals at high risk for HIV infection would benefit from ARV drug delivery systems with long duration and sustained/controlled drug release. Technological achievements in pharmaceutics and medicinal chemistry allow us to envision combining clinically advanced drug delivery technologies and extremely potent and long-acting ARV into drug delivery systems that could protect users from HIV for many months, and perhaps as long as a year. The objective of the Sustained Long-Acting Protection from HIV (SLAP-HIV) program is to test and clinically develop a long-acting drug delivery system of one of the following fourth generation ARV: cabotegravir, rilpivirine, tenofovir alafenamide fumarate, or the tenofovir analog CMX-157. Several parenteral drug delivery systems will be made and tested by three competing teams exploring three unique drug delivery platforms: reservoir implants, degradable implants, and controlled release injectables. We will compare our systems functionally for stability, manufacturability, duration, and pharmacokinetic and safety endpoints. We will work in parallel with high-risk groups to develop user based design input and criteria to inform the clinical development of the drug delivery systems. We will also investigate the acceptability of a wide variety of designs in high-risk individuals. A single lead formulation from each drug delivery project will be selected for further study of pharmacokinetics and pharmacodynamics in non-human primates. From these studies, a single lead formulation will be selected for clinical development, based on achieving a well-defined target product profile. Next, we will focus on studies required for an investigational new drug application (IND) along with the transfer of manufacturing methods to a contract research organization. We will conduct pharmacokinetics and pharmacodynamics studies in macaques to further study the prophylactic potential of the lead product and provide non-GLP support data for the IND. Finally, a Phase 1 clinical study will conclude the program to examine the safety, pharmacokinetics and acceptability of the lead ARV eluting drug delivery system. In total, these studies will advance our understanding of long-acting drug delivery systems and their ability to disrupt mechanisms of transmission. We have designed the program to ensure success and will be aided by the inclusion of many leading HIV experts, whose combined expertise spans drug delivery research, pharmaceutical development and HIV science. The impact of the product platforms developed from this research will extend beyond HIV PrEP and will advance our understanding of how to implement long-acting HIV therapy for those already infected, and to other therapeutic areas where long-acting systems are needed.